| 1. |
- Ajore, Ram, et al.
(författare)
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Functional dissection of inherited non-coding variation influencing multiple myeloma risk
- 2022
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Thousands of non-coding variants have been associated with increased risk of human diseases, yet the causal variants and their mechanisms-of-action remain obscure. In an integrative study combining massively parallel reporter assays (MPRA), expression analyses (eQTL, meQTL, PCHiC) and chromatin accessibility analyses in primary cells (caQTL), we investigate 1,039 variants associated with multiple myeloma (MM). We demonstrate that MM susceptibility is mediated by gene-regulatory changes in plasma cells and B-cells, and identify putative causal variants at six risk loci (SMARCD3, WAC, ELL2, CDCA7L, CEP120, and PREX1). Notably, three of these variants co-localize with significant plasma cell caQTLs, signaling the presence of causal activity at these precise genomic positions in an endogenous chromosomal context in vivo. Our results provide a systematic functional dissection of risk loci for a hematologic malignancy.
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| 2. |
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| 3. |
- Baranasic, Jurica, et al.
(författare)
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Germline variants of the genes involved in NF-kB activation are associated with the risk of COPD and lung cancer development
- 2023
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Ingår i: Acta Pharmaceutica. - 1330-0075. ; 73:2, s. 243-256
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Tidskriftsartikel (refereegranskat)abstract
- Chronic obstructive pulmonary disease (COPD) and lung cancer (LC) are closely related diseases associated with smoking history and dysregulated immune response. However, not all smokers develop the disease, indicating that genetic susceptibility could be important. Therefore, the aim of this study was to search for the potential overlapping genetic biomarkers, with a focus on single nucleotide polymorphisms (SNPs) located in the regulatory regions of immune-related genes. Additionally, the aim was to see if an identified SNP has potentially an effect on proinflamma-tory cytokine concentration in the serum of COPD patients. We extracted summary data of variants in 1511 immune-related genes from COPD and LC genome-wide association studies (GWAS) from the UK Biobank. The LC data had 203 cases, patients diagnosed with LC, and 360 938 controls, while COPD data had 1 897 cases and 359 297 controls. Assuming 1 association/gene, SNPs with a p-value < 3.3 × 10-5 were considered statistically significantly associated with the disease. We identified seven SNPs located in different genes (BAG6, BTNL2, TNF, HCP5, MICB, NCR3, ABCF1, TCF7L1) to be associated with the COPD risk and two with the LC risk (HLA-C, HLA-B), with statistical significance. We also identified two SNPs located in the IL2RA gene associated with LC (rs2386841; p = 1.86 × 10-4) and COPD (rs11256442; p = 9.79 × 10-3) but with lower significance. Functional studies conducted on COPD patients showed that RNA expression of IL2RA, IFNγand related proinflammatory cytokines in blood serum did not correlate with a specific genotype. Although results presented in this study do not fully support our hypothesis, it is worth to mention that the identified genes/SNPs that were associated with either COPD or LC risk, all were involved in the activation of the NF-κB transcription factor which is closely related to the regulation of the inflammatory response, a condition associated with both pathologies.
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| 4. |
- Blunk, Inga, et al.
(författare)
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Genomic imprinting analyses identify maternal effects as a cause of phenotypic variability in type 1 diabetes and rheumatoid arthritis
- 2020
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Imprinted genes, giving rise to parent-of-origin effects (POEs), have been hypothesised to affect type 1 diabetes (T1D) and rheumatoid arthritis (RA). However, maternal effects may also play a role. By using a mixed model that is able to simultaneously consider all kinds of POEs, the importance of POEs for the development of T1D and RA was investigated in a variance components analysis. The analysis was based on Swedish population-scale pedigree data. With P = 0.18 (T1D) and P = 0.26 (RA) imprinting variances were not significant. Explaining up to 19.00% (± 2.00%) and 15.00% (± 6.00%) of the phenotypic variance, the maternal environmental variance was significant for T1D (P = 1.60 × 10−24) and for RA (P = 0.02). For the first time, the existence of maternal genetic effects on RA was indicated, contributing up to 16.00% (± 3.00%) of the total variance. Environmental factors such as the social economic index, the number of offspring, birth year as well as their interactions with sex showed large effects.
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| 5. |
- Brandt, Jasmine, et al.
(författare)
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Thyroid-associated genetic polymorphisms in relation to breast cancer risk in the Malmö Diet and Cancer Study
- 2018
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136. ; 142:7, s. 1309-1321
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Tidskriftsartikel (refereegranskat)abstract
- Previous studies have suggested that thyroid function is associated with breast cancer risk, which could have an important clinical impact, as one in eight women will develop a thyroid disorder during her lifetime. However, the underlying pathomechanism behind the association is still unknown. We used the Malmö Diet and Cancer Study (a population-based prospective study consisting of 17,035 women) to examine 17 single nucleotide polymorphisms (SNPs) previously related to levels of free thyroxine (free T4) and thyroid peroxidase antibodies (TPO-Ab) as potential genetic risk factors for breast cancer. A baseline examination including free T4 and TPO-Ab levels was conducted at the time of inclusion. Genotyping was performed on 901 breast cancer patients and 3335 controls. Odds ratios (95% confidence intervals) for high free T4, TPO-Ab positivity, and breast cancer were calculated by logistic regression and adjusted for confounders. We identified one free T4-related SNP (rs2235544, D101 gene) that was significantly associated with both free T4 level and breast cancer risk. There was a suggested association between rs11675434 (TPO gene) and TPO-Ab level, and TPO-Ab-related rs11675434 (TPO), rs3094228 (HCP5), rs1033662 (no registered gene), and rs301806 (RERE) were associated with breast cancer risk. There was an indicated interaction between rs6485050 (no registered gene) and free T4 level in regards to breast cancer risk. This is the first study to suggest an association between thyroid-related SNPs and breast cancer risk. All SNPs have a biological plausibility of being associated with breast cancer risk, and may contribute to the genetic predisposition to breast cancer.
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| 6. |
- Brendle, Annika, et al.
(författare)
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Polymorphisms in predicted microRNA-binding sites in integrin genes and breast cancer ITGB4 as prognostic marker.
- 2008
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Ingår i: Carcinogenesis. - : Oxford University Press. - 0143-3334 .- 1460-2180. ; 29:7, s. 1394-1399
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Tidskriftsartikel (refereegranskat)abstract
- Integrins control the cell attachment to the extracellular matrix and play an important role in mediating cell proliferation, migration and survival. A number of important cancer-associated integrin genes can be regulated by microRNAs (miRNAs) that bind to their target sites in the 3' untranslated regions. We examined the effect of single-nucleotide polymorphisms (SNPs) in predicted miRNA target sites of six integrin genes (ITGA3, ITGA6, ITGAv, ITGB3, ITGB4 and ITGB5) on breast cancer (BC) risk and clinical outcome. Six SNPs were genotyped in 749 Swedish incident BC cases with detailed clinical data and up to 15 years of follow-up together with 1493 matched controls. We evaluated associations between genotypes and BC risk and clinical tumour characteristics. Survival probabilities were compared between different subgroups. As a novel finding, several SNPs seemed to associate with the hormone receptor status. The strongest association was observed between the A allele of the SNP rs743554 in the ITGB4 gene and oestrogen receptor-negative tumours [odds ratio 2.09, 95% confidence intervals (CIs) 1.19-3.67]. The same SNP was associated with survival. The A allele carriers had a worse survival compared with the wild-type genotype carriers (hazard ratio 2.11, 95% CIs 1.21-3.68). The poor survival was significantly associated with the aggressive tumour characteristics: high grade, lymph node metastasis and high stage. None of the SNPs was significantly associated with BC risk. As the ITGB4 SNP seems to influence tumour aggressiveness and survival, it may have prognostic value in the clinic.
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| 7. |
- Brendle, Annika, et al.
(författare)
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Single nucleotide polymorphisms in chromosomal instability genes and risk and clinical outcome of breast cancer : a Swedish prospective case-control study.
- 2009
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Ingår i: European journal of cancer (Oxford, England : 1990). - : Elsevier BV. - 1879-0852 .- 0959-8049. ; 45:3, s. 435-442
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Tidskriftsartikel (refereegranskat)abstract
- Chromosomal instability (CIN) is a major characteristic of many cancers. We investigated whether putatively functional single nucleotide polymorphisms (SNPs) in genes related to CIN (CENPF, ESPL1, NEK2, PTTG1, ZWILCH, ZWINT) affect breast cancer (BC) risk and clinical outcome in a Swedish cohort of 749 incident BC cases with detailed clinical data and up to 15 years of follow-up and 1493 matched controls. As a main observation, carriers of the A allele of the CENPF SNP rs438034 had a worse BC-specific survival compared to the wild type genotype GG carriers (hazard ratio (HR) 2.65, 95% confidence interval (CI) 1.19-5.90), although they were less likely to have regional lymph node metastases (odds ratio (OR) 0.71, 95% CI 0.51-1.01) and tumours of stage II-IV (OR 0.73, 95% CI 0.54-0.99). As there is increasing evidence that CENPF is associated with poor prognosis in patients with primary BC, further independent studies are needed to clarify the importance of genetic variation in the CENPF gene in the clinic.
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| 8. |
- Caliz, Rafael, et al.
(författare)
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Gender-Specific Effects of Genetic Variants within Th1 and Th17 Cell-Mediated Immune Response Genes on the Risk of Developing Rheumatoid Arthritis
- 2013
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:8
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Tidskriftsartikel (refereegranskat)abstract
- The present study was conducted to explore whether single nucleotide polymorphisms (SNPs) in Th1 and Th17 cell-mediated immune response genes differentially influence the risk of rheumatoid arthritis (RA) in women and men. In phase one, 27 functional/tagging polymorphisms in C-type lectins and MCP-1/CCR2 axis were genotyped in 458 RA patients and 512 controls. Carriers of Dectin-2(rs4264222T) allele had an increased risk of RA (OR = 1.47, 95% CI 1.10-1.96) whereas patients harboring the DC-SIGN(rs4804803G), MCP-1(rs1024611G), MCP-1(rs13900T) and MCP-1(rs4586C) alleles had a decreased risk of developing the disease (OR = 0.66, 95% CI 0.49-0.88; OR = 0.66, 95% CI 0.50-0.89; OR = 0.73, 95% CI 0.55-0.97 and OR = 0.68, 95% CI 0.51-0.91). Interestingly, significant gender-specific differences were observed for Dectin-2(rs4264222) and Dectin-2(rs7134303): women carrying the Dectin-2(rs4264222T) and Dectin-2(rs7134303G) alleles had an increased risk of RA (OR = 1.93, 95% CI 1.34-2.79 and OR = 1.90, 95% CI 1.29-2.80). Also five other SNPs showed significant associations only with one gender: women carrying the MCP-1(rs1024611G), MCP-1(rs13900T) and MCP-1(rs4586C) alleles had a decreased risk of RA (OR = 0.61, 95% CI 0.43-0.87; OR = 0.67, 95% CI 0.47-0.95 and OR = 0.60, 95% CI 0.42-0.86). In men, carriers of the DC-SIGN(rs2287886A) allele had an increased risk of RA (OR = 1.70, 95% CI 1.03-2.78), whereas carriers of the DC-SIGN(rs4804803G) had a decreased risk of developing the disease (OR = 0.53, 95% CI 0.32-0.89). In phase 2, we genotyped these SNPs in 754 RA patients and 519 controls, leading to consistent gender-specific associations for Dectin-2(rs4264222), MCP-1(rs1024611), MCP-1(rs13900) and DC-SIGN(rs4804803) polymorphisms in the pooled sample (OR = 1.38, 95% CI 1.08-1.77; OR = 0.74, 95% CI 0.58-0.94; OR = 0.76, 95% CI 0.59-0.97 and OR = 0.56, 95% CI 0.34-0.93). SNP-SNP interaction analysis of significant SNPs also showed a significant two-locus interaction model in women that was not seen in men. This model consisted of Dectin-2(rs4264222) and Dectin-2(rs7134303) SNPs and suggested a synergistic effect between the variants. These findings suggest that Dectin-2, MCP-1 and DC-SIGN polymorphisms may, at least in part, account for gender-associated differences in susceptibility to RA.
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| 9. |
- Campa, Daniele, et al.
(författare)
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A Comprehensive Investigation on Common Polymorphisms in the MDR1/ABCB1 Transporter Gene and Susceptibility to Colorectal Cancer
- 2012
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 7:3
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Tidskriftsartikel (refereegranskat)abstract
- ATP Binding Cassette B1 (ABCB1) is a transporter with a broad substrate specificity involved in the elimination of several carcinogens from the gut. Several polymorphic variants within the ABCB1 gene have been reported as modulators of ABCB1-mediated transport. We investigated the impact of ABCB1 genetic variants on colorectal cancer (CRC) risk. A hybrid tagging/functional approach was performed to select 28 single nucleotide polymorphisms (SNPs) that were genotyped in 1,321 Czech subjects, 699 CRC cases and 622 controls. In addition, six potentially functional SNPs were genotyped in 3,662 German subjects, 1,809 cases and 1,853 controls from the DACHS study. We found that three functional SNPs (rs1202168, rs1045642 and rs868755) were associated with CRC risk in the German population. Carriers of the rs1202168_T and rs868755_T alleles had an increased risk for CRC (P-trend = 0.016 and 0.029, respectively), while individuals bearing the rs1045642_C allele showed a decreased risk of CRC (P-trend = 0.022). We sought to replicate the most significant results in an independent case-control study of 3,803 subjects, 2,169 cases and 1,634 controls carried out in the North of Germany. None of the SNPs tested were significantly associated with CRC risk in the replication study. In conclusion, in this study of about 8,800 individuals we show that ABCB1 gene polymorphisms play at best a minor role in the susceptibility to CRC.
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| 10. |
- Campa, Daniele, et al.
(författare)
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Polymorphisms of genes coding for ghrelin and its receptor in relation to colorectal cancer risk: a two-step gene-wide case-control study
- 2010
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Ingår i: BMC Gastroenterology. - 1471-230X. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Background: Ghrelin, an endogenous ligand for the growth hormone secretagogue receptor (GHSR), has two major functions: the stimulation of the growth hormone production and the stimulation of food intake. Accumulating evidence also indicates a role of ghrelin in cancer development. Methods: We conducted a case-control study to examine the association of common genetic variants in the genes coding for ghrelin (GHRL) and its receptor (GHSR) with colorectal cancer risk. Pairwise tagging was used to select the 11 polymorphisms included in the study. The selected polymorphisms were genotyped in 680 cases and 593 controls from the Czech Republic. Results: We found two SNPs associated with lower risk of colorectal cancer, namely SNPs rs27647 and rs35683. We replicated the two hits, in additional 569 cases and 726 controls from Germany. Conclusion: A joint analysis of the two populations indicated that the T allele of rs27647 SNP exerted a protective borderline effect (P-trend = 0.004).
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| 11. |
- Campo, Chiara, et al.
(författare)
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Bortezomib-induced peripheral neuropathy : A genome-wide association study on multiple myeloma patients
- 2018
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Ingår i: Hematological Oncology. - : Wiley. - 0278-0232. ; 36:1, s. 232-237
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Tidskriftsartikel (refereegranskat)abstract
- The proteasome-inhibitor bortezomib was introduced into the treatment of multiple myeloma more than a decade ago. It is clinically beneficial, but peripheral neuropathy (PNP) is a side effect that may limit its use in some patients. To examine the possible genetic predisposing factors to PNP, we performed a genome-wide association study on 646 bortezomib-treated German multiple myeloma patients. Our aim was to identify genetic risk variants associated with the development of PNP as a serious side effect of the treatment. We identified 4 new promising loci for bortezomib-induced PNP at 4q34.3 (rs6552496), 5q14.1 (rs12521798), 16q23.3 (rs8060632), and 18q21.2 (rs17748074). Even though the results did not reach genome-wide significance level, they support the idea of previous studies, suggesting a genetic basis for neurotoxicity. The identified single nucleotide polymorphisms map to genes or next to genes involved in the development and function of the nervous system (CDH13, DCC, and TENM3). As possible functional clues, 2 of the variants, rs12521798 and rs17748074, affect enhancer histone marks in the brain. The rs12521798 may also impact expression of THBS4, which affects specific signal trasduction pathways in the nervous system. Further research is needed to clarify the mechanism of action of the identified single nucleotide polymorphisms in the development of drug-induced PNP and to functionally validate our in silico predictions.
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| 12. |
- Campo, Chiara, et al.
(författare)
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Genetic Susceptibility to Bortezomib-Induced Peripheral Neuroropathy : Replication of the Reported Candidate Susceptibility Loci
- 2017
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Ingår i: Neurochemical Research. - : Springer Science and Business Media LLC. - 0364-3190 .- 1573-6903. ; 42:3, s. 925-931
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Tidskriftsartikel (refereegranskat)abstract
- The introduction of proteasome inhibitors in the treatment of multiple myeloma (MM) patients has been a therapeutic success. Peripheral neuropathy (PNP) remains one of the most frequent side-effects experienced by patients who receive these novel agents. Recent investigations on the mechanisms of PNP in patients treated with bortezomib have suggested genetic susceptibility to neurotoxicity. We used data from a genome-wide association study conducted on 646 bortezomib-treated German MM patients to replicate the previously reported associations between single-nucleotide polymorphisms (SNPs) in candidate genes and PNP in MM patients, including 298 SNPs with a nominal significance (p value <0.05). Twelve associations were confirmed at a significance level p value <0.05. The corresponding SNPs are located in genes involved in drug metabolism (ABCC1, ABCC6), development and function of the nervous system (POGZ, NFAT pathway, EDN1), modulation of immune responses (IL17RD, IL10RA) and the NF-κB signaling pathway (PSMB4, BTCR, F2). We systematically investigated functional consequences of those variants using several bioinformatics tools, such as HaploRegV4.1, RegulomeDB and UCSC Genome Browser. Expression quantitative trait loci (eQTL) data suggested that some of the identified SNPs might influence gene expression through a differential recruitment of transcription factors. In conclusion, we confirmed some of the recently reported associations between germline variation and PNP. Elucidating the mechanisms underlying these associations will contribute to the development of new strategies for the prevention or reduction of PNP.
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| 13. |
- Carrai, Maura, et al.
(författare)
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Association Between TAS2R38 Gene Polymorphisms and Colorectal Cancer Risk: A Case-Control Study in Two Independent Populations of Caucasian Origin
- 2011
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 6:6
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Tidskriftsartikel (refereegranskat)abstract
- Molecular sensing in the lingual mucosa and in the gastro-intestinal tract play a role in the detection of ingested harmful drugs and toxins. Therefore, genetic polymorphisms affecting the capability of initiating these responses may be critical for the subsequent efficiency of avoiding and/or eliminating possible threats to the organism. By using a tagging approach in the region of Taste Receptor 2R38 (TAS2R38) gene, we investigated all the common genetic variation of this gene region in relation to colorectal cancer risk with a case-control study in a German population (709 controls and 602 cases) and in a Czech population (623 controls and 601 cases). We found that there were no significant associations between individual SNPs of the TAS2R38 gene and colorectal cancer in the Czech or in the German population, nor in the joint analysis. However, when we analyzed the diplotypes and the phenotypes we found that the non-taster group had an increased risk of colorectal cancer in comparison to the taster group. This association was borderline significant in the Czech population, (OR = 1.28, 95% CI 0.99-1.67; P-value = 0.058) and statistically significant in the German population (OR = 1.36, 95% CI 1.06-1.75; P-value = 0.016) and in the joint analysis (OR = 1.34, 95% CI 1.12-1.61; P-value = 0.001). In conclusion, we found a suggestive association between the human bitter tasting phenotype and the risk of CRC in two different populations of Caucasian origin.
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| 14. |
- Castro, Felipe A, et al.
(författare)
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Association of HLA-DRB1, interleukin-6 and cyclin D1 polymorphisms with cervical cancer in the Swedish population-A candidate gene approach.
- 2009
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Ingår i: International Journal of Cancer. - : John Wiley & Sons. - 0020-7136 .- 1097-0215. ; 125:8, s. 1851-1858
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Tidskriftsartikel (refereegranskat)abstract
- High-risk human papillomavirus (hrHPV) infection is the major risk factor for cervical cancer (CxCa). The role of genetic susceptibility in the disease has been suggested, but the existing data lack consistency. We conducted a nested case-control study on 973 CxCa cases and 1,763 matched controls, from two Swedish population-based cohorts to examine the association of common genetic variants with CxCa risk. Human leukocyte antigen (HLA) alleles and 24 other polymorphisms in 14 genes were selected on the basis of reported association or mechanistic plausibility with an HPV infection or cervical cancer development. Genotyping was conducted using multiplex PCR and Luminex technology. A significant association of CxCa with various polymorphisms was observed: rs1800797 in the IL-6 gene (odds ratio [OR] = 0.88, 95% confidence intervals [CI]: 0.79-0.99); rs1041981 in the LTA gene (OR = 0.87, 95% CI: 0.78-0.98), and rs9344 in the CCND1 gene (OR = 1.14, 95% CI: 1.02-1.27), for those individuals carrying the rare allele. Additionally, the alleles 0401 and 1501 of the HLA class II DRB1 locus were associated with an increased risk (OR = 1.23, 95% CI: 1.04-1.45 and OR = 1.29, 95% CI: 1.11-1.50, respectively), and allele 1301 was associated with decreased risk (OR = 0.59, 95% CI: 0.47-0.73). The effects of CCND1 and the HLA*DRB1 alleles were independent of the effect of smoking. We did not find any association of risk with polymorphisms in genes related to the innate immune system. In conclusion, our study provides evidence for genetic susceptibility to CxCa due to variations in genes involved in the immune system and in cell cycle. (c) 2009 UICC.
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| 15. |
- Castro, Felipe A., et al.
(författare)
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Increased Risk of Hepatobiliary Cancers After Hospitalization for Autoimmune Disease
- 2014
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Ingår i: Clinical Gastroenterology and Hepatology. - : Elsevier BV. - 1542-7714 .- 1542-3565. ; 12:6, s. 1038-1045
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND & AIMS: Some autoimmune diseases are associated with increased risk of liver cancer. However, there has been no comprehensive evaluation of autoimmune diseases among patients who develop different subtypes of hepatobiliary cancer. We examined the association between autoimmune diseases and cancers of the liver and biliary tract in the Swedish population. METHODS: We analyzed data from national datasets at the Center for Primary Health Care Research (Lund University, Sweden). Data on patients with autoimmune disorders were retrieved from the Swedish Hospital Discharge Register, from 1964 through 2008; 33 diseases were evaluated. Hepatobiliary cancer cases were retrieved from the Swedish Cancer Registry. We calculated standardized incidence ratios (SIRs) and hazard ratios for incident cancers and deaths from hepatobiliary cancers. RESULTS: Among 402,462 patients with autoimmune disorders, 582 were diagnosed with primary liver cancer, 330 with gallbladder cancer, 115 with extrahepatic bile duct cancer, and 43 with ampulla of Vater cancers. We identified 14 autoimmune conditions that were significantly associated with increased risk of primary liver cancer (overall SIR [any autoimmune disease], 2.1; 95% confidence interval [CI], 2.0-2.3), 5 conditions associated with gallbladder cancer (overall SIR, 1.3; 95% CI, 1.1-1.4), and 3 associated with extrahepatic bile duct cancer (overall SIR, 1.6; 95% CI, 1.3-1.9). The autoimmune disorders with the strongest association with primary liver cancer were primary biliary cirrhosis (SIR, 39.5; 95% CI, 28.2-53.8) and autoimmune hepatitis (SIR, 29.0; 95% CI, 9.1-68.2); ulcerative colitis was strongly associated with extrahepatic bile duct cancer (SIR, 5.6; 95% CI, 3.6-8.4). Celiac disease, Crohn's disease, systemic sclerosis, and ulcerative colitis were associated with at least 2 types of cancer. Increased hazard ratios were observed only for patients with biliary tract cancer who had been hospitalized for autoimmune conditions. CONCLUSIONS: In a study of the Swedish population, we identified an increased risk of hepatobiliary cancers among individuals diagnosed with autoimmune disease. Associations among different cancer types indicate that shared immunomodulatory mechanisms determine susceptibility to hepatobiliary cancer.
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| 16. |
- Castro, F. A., et al.
(författare)
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TLR-3 polymorphism is an independent prognostic marker for stage II colorectal cancer
- 2011
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Ingår i: European Journal of Cancer. - : Elsevier BV. - 1879-0852 .- 0959-8049. ; 47:8, s. 1203-1210
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Tidskriftsartikel (refereegranskat)abstract
- Background: Clinicopathologic stage is still the main parameter to evaluate the prognosis of newly diagnosed colorectal cancer (CRC) patients. Although molecular markers have been suggested for follow up of treated CRC patients, their complete clinical application is still under evaluation. Materials and methods: To evaluate the association of immune-related genes with CRC prognosis and survival, a total of 19 single nucleotide polymorphisms (SNPs) were genotyped in 614 German patients within the Kiel cohort (POPGEN). Results: A promoter variant (rs1800872) in the Interleukin-10 (IL-10) gene was associated with an increased lymph node metastasis involvement [odds ratio (OR) = 2.1, 95% confidence interval (CI) = 1.03-4.2, for carriers of the TT genotype]. More importantly, among 582 followed up patients the SNP rs3775291 in the toll-like receptor 3 (TLR-3) gene was associated with CRC specific survival (150 events). Patients carrying the TT genotype had a 93% increased risk of death compared with the CC carriers [hazard ratio (HR) = 1.93, 95% CI 1.14-3.281. The observed effect of the TLR-3 variant was restricted to stage II patients (HR = 4.14, 95% CI 1.24-13.84) and to patients who did not receive adjuvant therapy (HR = 3.2, 95% CI 1.4-7.7). Conclusions: Our results may provide additional candidates for risk assessment in stage II CRC patients for treatment decision. Further validation of the presented findings is warranted. (C) 2010 Elsevier Ltd. All rights reserved.
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| 17. |
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| 18. |
- Catalano, Calogerina, et al.
(författare)
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Epistatic effect of TLR3 and cGAS-STING-IKKε-TBK1-IFN signaling variants on colorectal cancer risk
- 2020
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Ingår i: Cancer Medicine. - : Wiley. - 2045-7634. ; 9:4, s. 1473-1484
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Tidskriftsartikel (refereegranskat)abstract
- Objective: The TLR3/cGAS-STING-IFN signaling has recently been reported to be disturbed in colorectal cancer due to deregulated expression of the genes involved. Our study aimed to investigate the influence of potential regulatory variants in these genes on the risk of sporadic colorectal cancer (CRC) in a Czech cohort of 1424 CRC patients and 1114 healthy controls. Methods: The variants in the TLR3, CGAS, TMEM173, IKBKE, and TBK1 genes were selected using various online bioinformatic tools, such as UCSC browser, HaploReg, Regulome DB, Gtex Portal, SIFT, PolyPhen2, and miRNA prediction tools. Results: Logistic regression analysis adjusted for age and sex detected a nominal association between CRC risk and three variants, CGAS rs72960018 (OR: 1.68, 95% CI: 1.11-2.53, P-value =.01), CGAS rs9352000 (OR: 2.02, 95% CI: 1.07-3.84, P-value =.03) and TMEM173 rs13153461 (OR: 1.53, 95% CI: 1.03-2.27, P-value =.03). Their cumulative effect revealed a threefold increased CRC risk in carriers of 5-6 risk alleles compared to those with 0-2 risk alleles. Epistatic interactions between these genes and the previously genotyped IFNAR1, IFNAR2, IFNA, IFNB, IFNK, IFNW, IRF3, and IRF7 genes, were computed to test their effect on CRC risk. Overall, we obtained nine pair-wise interactions within and between the CGAS, TMEM173, IKBKE, and TBK1 genes. Two of them remained statistically significant after Bonferroni correction. Additional 52 interactions were observed when IFN variants were added to the analysis. Conclusions: Our data suggest that epistatic interactions and a high number of risk alleles may play an important role in CRC carcinogenesis, offering novel biological understanding for the CRC management.
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| 19. |
- Catalano, Calogerina, et al.
(författare)
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Investigation of single and synergic effects of NLRC5 and PD-L1 variants on the risk of colorectal cancer
- 2018
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 13:2
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Tidskriftsartikel (refereegranskat)abstract
- Constitutive activation of interferon signaling pathways has been reported in colorectal cancer (CRC), leading to a strong CD8+ T cell response through stimulation of NLRC5 expression. Primed CD8+ T cell expansion, however, may be negatively regulated by PD-L1 expression. Additionally, aberrant PD-L1 expression enables cancer cells to escape the immune attack. Our study aimed to select potential regulatory variants in the NLRC5 and PD-L1 genes by using several online in silico tools, such as UCSC browser, HaploReg, Regulome DB, Gtex Portal, microRNA and transcription factor binding site prediction tools and to investigate their influence on CRC risk in a Czech cohort of 1424 CRC patients and 1114 healthy controls. Logistic regression analysis adjusted for age and gender reported a moderate association between rectal cancer risk and two NLRC5 SNPs, rs1684575 T>G (OR: 1.60, 95% CI: 1.13–2.27, recessive model) and rs3751710 (OR: 0.70, 95% CI: 0.51–0.96, dominant model). Given that a combination of genetic variants, rather than a single polymorphism, may explain better the genetic etiology of CRC, we studied the interplay between the variants within NLRC5, PD-L1 and the previously genotyped IFNGR1 and IFNGR2 variants, to evaluate their involvement in the risk of CRC development. Overall we obtained 18 pairwise interactions within and between the NLRC5 ad PD-L1 genes and 6 more when IFNGR variants were added. Thirteen out of the 24 interactions were below the threshold for the FDR calculated and controlled at an arbitrary level q*<0.10. Furthermore, the interaction IFNGR2 rs1059293 C>T—NLRC5 rs289747 G>A (P<0.0001) remained statistically significant even after Bonferroni correction. Our data suggest that not only a single genetic variant but also an interaction between two or more variants within genes involved in immune regulation may play important roles in the onset of CRC, providing therefore novel biological information, which could eventually improve CRC risk management but also PD-1-based immunotherapy in CRC.
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| 20. |
- Catalano, Calogerina, et al.
(författare)
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Short article : Influence of regulatory NLRC5 variants on colorectal cancer survival and 5-fluorouracil-based chemotherapy
- 2018
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Ingår i: European Journal of Gastroenterology and Hepatology. - 0954-691X. ; 30:8, s. 838-842
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Tidskriftsartikel (refereegranskat)abstract
- Background NLRC5 is an interferon γ-inducible protein, which plays a role in immune surveillance with a potential influence on cancer survival. Objective We aimed to evaluate the effect of potential regulatory variants in NLRC5 on overall survival and survival after 5-fluorouracil (5-FU)-based therapy of colorectal cancer (CRC) patients. Patients and methods We carried out a case-only study in a Czech population of 589 cases; 232 received 5-FU-based therapy. Eleven variants within NLRC5 were selected using in-silico tools. Associations between polymorphisms and survival were assessed by Cox regression analysis adjusting for age at diagnosis, sex, and TNM stage. Survival curves were derived using the Kaplan-Meier method. Results Two variants showed a significant association with survival. All patients and metastasis-free patients at the time of diagnosis (pM0) who were homozygous carriers of the minor allele of rs27194 had a decreased overall survival (OS all and OS pM0) and event-free survival (EFS pM0) under a recessive model (OS all P=0.003, OS pM0 P=0.005, EFS pM0 P=0.01, respectively). OS was also decreased for all patients and for pM0 patients who carried at least one minor allele of rs289747 (OS all P=0.03 and OS pM0 P=0.003, respectively). Among CRC patients, who underwent a 5-FU-based adjuvant regimen, rs12445252 was associated with OS all, OS pM0 and EFS pM0, according to the dosage of the minor allele T (OS all P=0.0004, OS pM0 P=0.0001, EFS pM0 P=0.008, respectively). Conclusion Our results showed that polymorphisms in NLRC5 may be used as prognostic markers of survival of CRC patients, as well as for survival in response to 5-FU treatment.
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| 21. |
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| 22. |
- Chattopadhyay, Subhayan, et al.
(författare)
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Enrichment of B cell receptor signaling and epidermal growth factor receptor pathways in monoclonal gammopathy of undetermined significance : a genome-wide genetic interaction study
- 2018
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Ingår i: Molecular Medicine. - : Springer Science and Business Media LLC. - 1528-3658 .- 1076-1551. ; 24:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Recent identification of 10 germline variants predisposing to monoclonal gammopathy of undetermined significance (MGUS) explicates genetic dependency of this asymptomatic precursor condition with multiple myeloma (MM). Yet much of genetic burden as well as functional links remain unexplained. We propose a workflow to expand the search for susceptibility loci with genome-wide interaction and for subsequent identification of genetic clusters and pathways.METHODS: Polygenic interaction analysis on 243 cases/1285 controls identified 14 paired risk loci belonging to unique chromosomal bands which were then replicated in two independent sets (case only study, 82 individuals; case/control study 236 cases/ 2484 controls). Further investigation on gene-set enrichment, regulatory pathway and genetic network was carried out with stand-alone in silico tools separately for both interaction and genome-wide association study-detected risk loci.RESULTS: Intronic-PREX1 (20q13.13), a reported locus predisposing to MM was confirmed to have contribution to excess MGUS risk in interaction with SETBP1, a well-established candidate predisposing to myeloid malignancies. Pathway enrichment showed B cell receptor signaling pathway (P < 5.3 × 10- 3) downstream to allograft rejection pathway (P < 5.6 × 10- 4) and autoimmune thyroid disease pathway (P < 9.3 × 10- 4) as well as epidermal growth factor receptor regulation pathway (P < 2.4 × 10- 2) to be differentially regulated. Oncogene ALK and CDH2 were also identified to be moderately interacting with rs10251201 and rs16966921, two previously reported risk loci for MGUS.CONCLUSIONS: We described novel pathways and variants potentially causal for MGUS. The methodology thus proposed to facilitate our search streamlines risk locus-based interaction, genetic network and pathway enrichment analyses.
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| 23. |
- Chattopadhyay, Subhayan, et al.
(författare)
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Genome-wide interaction and pathway-based identification of key regulators in multiple myeloma
- 2019
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Ingår i: Communications Biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 2:1
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Tidskriftsartikel (refereegranskat)abstract
- Inherited genetic susceptibility to multiple myeloma has been investigated in a number of studies. Although 23 individual risk loci have been identified, much of the genetic heritability remains unknown. Here we carried out genome-wide interaction analyses on two European cohorts accounting for 3,999 cases and 7,266 controls and characterized genetic susceptibility to multiple myeloma with subsequent meta-analysis that discovered 16 unique interacting loci. These risk loci along with previously known variants explain 17% of the heritability in liability scale. The genes associated with the interacting loci were found to be enriched in transforming growth factor beta signaling and circadian rhythm regulation pathways suggesting immunoglobulin trait modulation, TH17 cell differentiation and bone morphogenesis as mechanistic links between the predisposition markers and intrinsic multiple myeloma biology. Further tissue/cell-type enrichment analysis associated the discovered genes with hemic-immune system tissue types and immune-related cell types indicating overall involvement in immune response.
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| 24. |
- Chattopadhyay, Subhayan, et al.
(författare)
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Impact of family history of cancer on risk and mortality of second cancers in patients with prostate cancer
- 2019
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Ingår i: Prostate Cancer and Prostatic Diseases. - : Springer Science and Business Media LLC. - 1365-7852 .- 1476-5608. ; 22:1, s. 143-149
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Tidskriftsartikel (refereegranskat)abstract
- Background: Survival rates are increasing in patients with prostate cancer, and second primary cancers (SPCs) are becoming more common in these patients. However, the etiology and clinical consequences of SPCs are not well-known. We define the impact of family history on SPC and causes of mortality in these patients. Patients and methods: A nation-wide cohort study based on the Swedish Family-Cancer Database covering 4.4 million men and 80,449 prostate cancers diagnosed between 1990 and 2015. Relative risks (RRs) and cumulative incidence for SPCs and for familial SPC were calculated for prostate cancer patients. Results: SPC was diagnosed in 6,396 men and more than a third of these patients had a first-degree family history of any cancer; the familial risk was 1.37 (95% CI: 1.27–1.40), compared to 1.10 (1.08–1.16), without a family history. Cumulative incidence by the age of 83 years reached 21% for prostate cancer alone, 28% in those with SPC, and 35% in patients with SPC and family history. Family history was associated with the risk of seven specific SPCs, including colorectal, lung, kidney, bladder and skin (both melanoma and squamous cell) cancers, and leukemia. Colorectal and lung cancers were common SPCs, and family history doubled the risk of these SPCs. In patients with SPC, half of all causes of death were due to SPC and only 12.77% were due to prostate cancer. Most deaths in SPC were caused by lung and colorectal cancers. Conclusions: SPCs were an important cause of death in patients with prostate cancer and family history was an important risk factor for SPCs. Prevention of SPC should be essential when prostate cancer survival rates are being improved and this could start by conducting a thorough assessment of family history at the time of prostate cancer diagnosis.
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| 25. |
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